(R)-5-(二丙基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-2(1H)-酮 | 132874-73-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: (R)-5-(二丙基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-2(1H)-酮
• 英文名称: U 86170
• 英文别名: (R)-5-(dipropylamino)-5,6-dihydro-4H-imidazo<4,5-1-ij>quinolin-2(1H)-one；(R)-5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one；(R)-5-(dipropylamino)-5,6-dihydro-4H-imidazo(4,5-1-ij)quinolin-2(1H)-one；5-(Dipropylamino)-5,6-dihydro-4H-imidazo-(5,1ij)quinolin-2(1H)-one；(10R)-10-(dipropylamino)-1,3-diazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-2-one
• CAS: 132874-73-8
• 化学式: C₁₆H₂₃N₃O
• 分子量: 273.378
• InChiKey: UCZYAFAFGFTZEW-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (R)-5-(二丙基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-2(1H)-酮 、 N-(4-bromobutyl)-1H-indole-2-carboxamide 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以17%的产率得到(R)-N-(4-(5-(dipropylamino)-2-oxo-5,6-dihydro-4H-imidazo-[4,5,1-ij]quinolin-1(2H)-yl)butyl)-1H-indole-2-carboxamide
  参考文献：
  名称：

  Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism

  摘要：

  The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-S-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G(i/o)-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D-2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.

  DOI：

  10.1021/acs.jmedchem.6b01875
• 作为产物：
  描述：

  N-苄氧羰基-D-苯丙氨酸 在 palladium 10% on activated carbon 、 10 wt% Pd(OH)2 on carbon 、 氢气 、 dimethyl sulfide borane 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 potassium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 、 [双(三氟乙酰氧基)碘]苯 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， -40.0~65.0 ℃ 、344.75 kPa 条件下， 反应 225.17h， 生成 (R)-5-(二丙基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-2(1H)-酮
  参考文献：
  名称：

  （R）-5-（甲氨基）-5,6-二氢-4 H-咪唑并[4,5,1- ij ]喹啉-2（1 H）-one（舒马尼罗）的新类似物为多巴胺D 2提供了线索/ D 3受体激动剂选择性

  摘要：

  sumanirole的新的1-，5-，和8-取代的类似物（1），多巴胺d 2 / d 3受体（d 2 R / d 3 R）激动剂，合成。当与激动剂放射性配体[ 3 H] 7-羟基-N，N-二丙基-2-氨基四氢萘（7-OH-DPAT）竞争测定时，在D 2 R和D 3 R处的结合亲和力都较高。[ 3 H] N-甲基哌啶。尽管1被确认为D 2R-优先激动剂，它在结合和功能研究中的选择性比以前报道的要低。在G o BRET和有丝分裂发生功能测定中，所有类似物均被确定为D 2 R / D 3 R激动剂。在D 3 R处检测到N -1-取代的类似物的功效下降。相比之下，N -5-烷基取代的类似物，尤其是正丁基芳基酰胺（22b和22c），均显示出改善的亲和力。 D 2 R超过1既不损失功效也不增加选择性。计算建模为D提供了结构基础2的1R选择性1，示出了如何在高度同源的正构结合位点的细微差别（OBS）中差异影响d

  DOI：

  10.1021/acs.jmedchem.5b01612

文献信息

• Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism
  作者：Alessandro Bonifazi、Hideaki Yano、Michael P. Ellenberger、Ludovic Muller、Vivek Kumar、Mu-Fa Zou、Ning Sheng Cai、Adrian M. Guerrero、Amina S. Woods、Lei Shi、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.6b01875

  日期：2017.4.13

  The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-S-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G(i/o)-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D-2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.
• Novel Analogues of (<i>R</i>)-5-(Methylamino)-5,6-dihydro-4<i>H</i>-imidazo[4,5,1-<i>ij</i>]quinolin-2(1<i>H</i>)-one (Sumanirole) Provide Clues to Dopamine D₂/D₃ Receptor Agonist Selectivity
  作者：Mu-Fa Zou、Thomas M. Keck、Vivek Kumar、Prashant Donthamsetti、Mayako Michino、Caitlin Burzynski、Catherine Schweppe、Alessandro Bonifazi、R. Benjamin Free、David R. Sibley、Aaron Janowsky、Lei Shi、Jonathan A. Javitch、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.5b01612

  日期：2016.4.14

  in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a

  sumanirole的新的1-，5-，和8-取代的类似物（1），多巴胺d 2 / d 3受体（d 2 R / d 3 R）激动剂，合成。当与激动剂放射性配体[ 3 H] 7-羟基-N，N-二丙基-2-氨基四氢萘（7-OH-DPAT）竞争测定时，在D 2 R和D 3 R处的结合亲和力都较高。[ 3 H] N-甲基哌啶。尽管1被确认为D 2R-优先激动剂，它在结合和功能研究中的选择性比以前报道的要低。在G o BRET和有丝分裂发生功能测定中，所有类似物均被确定为D 2 R / D 3 R激动剂。在D 3 R处检测到N -1-取代的类似物的功效下降。相比之下，N -5-烷基取代的类似物，尤其是正丁基芳基酰胺（22b和22c），均显示出改善的亲和力。 D 2 R超过1既不损失功效也不增加选择性。计算建模为D提供了结构基础2的1R选择性1，示出了如何在高度同源的正构结合位点的细微差别（OBS）中差异影响d